Process of optical resolution of racemic glutamic acid salts



United States Patent 3,365,492 PROCESS OF OPTICAL RESDLUTION 0F RACEMIC GLUTAMIC ACKD SALTS Gentaro Noyori, Hidemoto Kurokawa, and Teilro Watanabe, Tokyo, Japan, assignors to The Noguchi Institute, Itabashi-ku, Tokyo, Japan, a corporation of Japan No Drawing. Filed Mar. 23, 1964, Ser. No. 354,110 Claims priority, application Japan, Mar. 21, 1963, 38/ 14,895 18 Claims. (Cl. 260-534) This invention relates to a process for resolving glutamic acid salts. More particularly, this invention relates to a process for resolving racemic glutamic acid salts comprising treating a supersaturated solution of a racemic glutamic acid salt with either L- or D-form as desired, which may be introduced as a solution, thereby causing the separation of crystals of the optically active glutamic acid salt of the same type as that employed for the treatment, and finally recovering the resulting optically active glutamic acid salt. Recently, attempts have been made to produce glutamic acid through synthesis. In these cases, however, only racemic compounds are formed, the use of which are negligible in industry. It is desirable to resolve such racemic compounds into the two optically active isomers. Thus resolved -L-glutamic acid is consumed in large amounts in the form of the sodium salt as a flavor intensifier.

Various methods for resolving racemic glutamic acid through the selective crystallization method have been proposed since they use no expensive reagents.

These conventional processes generally consist of adding seed crystals of an optically active .L- or D-glutam-ic acid to a supersaturated solution of racemic glutamic acid, or continuously feeding a supersaturated solution of racemic acid into a container provided with seeding crystals, which cause the selective growth of crystals of the active form, and recovering the resulting optically active crystals. For carrying out these processes successfully, the seed crystals must be optically pure and preferably be of uniform crystal size, and must have been prepared cautiously. Seed crystals containing substantially no racemic acid and thus having high optical purity must have been employed. Furthermore, complicated steps such as crushing and screening have been necessary for obtaining seed crystals with a uniform crystal size distribution. The problems of efliciently obtaining crystals of an optically active isomer of high purity by promoting crystallization of the desired isomer and preventing contamination by the undesired isomer on a commercially feasible scale have never been sufliciently disposed of even with these processes.

The object of the present invention is to provide a process for resolving salts of glutamic acid on a commercial scale, which process is simple to operate. Another object is to provide a resolution process which re quires no complicated steps for producing highly purified seed crystal of homogeneous crystal size to be employed for resolution through selective crystallization. Another object is to provide a simplified resolution process with addition of liquid and mixing etc. without employing seed crystal in the initiation of resolution.

Still another object is to provide an eflicient resolution process for-obtaining highly purified salts of an optically active isomer from a solution, which process is simple to control through formation of homogeneous tine nuclear crystals.

Still another object is to provide a resolution process characterized by accelerated formation of crystal nuclei by treatment with ultrasonic waves, and by good reproducibility.

A further object is to provide a resolution process in which the time required for maximum resolution, and crystal size are easy to control.

We have discovered that a solution of an optically active glutamic acid salt introduced into and stirred with a supersaturated solution of the corresponding racemic glutamic acid salt causes the formation of fine crystalline nuclei of the optically active isomer in said supersaturated solution. These nuclei grow rapidly, and the amount of the isomer continues to increase over a period of time until crystallization of another undesirable isomer begins. This second crystallization results in a lowering of the optical purity, and the proportion of the desired optical isomer in spite of the continued increase in the amount of crystals. The amount of the desired optically active isomer in the form of crystalline solid phase continues to increase with time up to a maximum value, after which the desired material becomes gradually more and more contaminated with another isomer. Accordingly, one of the above-mentioned objects of this invention, i.e., to carry out an efficient resolution and to obtain optically active crystals with higher level of optical purity may be achieved by separating the solid phase crystalline material from the liquid phase just at or somewhat before the time when the said maximal amount of optically pure crystals have been accumulated.

Since many crystalline nuclei of the optically active isomer simultaneously develop and grow rapidly and uniformly, the amount of the desired optically active crys tals of high purity was found to attain a maximum value after a specified period of time with a controlled degree of supersaturation of racemic acid salt and the concentration and the amount of the solution containing the desired isomer, thus making possible an efiicien-t resolution which depends solely on time. Thus the period of time necessary for effecting such resolution may be regulated by suitably selecting the degree of supersaturation and the amount and concentration of the solution containing the desired optically active isomer.

Based on these findings, we have succeeded in establishing a simpler and more advantageous process of resolution employable on a commercial scale.

Since no absolute optical purity is required for the optically active glutamic acid to be employed in solution according to this invention, and contamination of racemate is allowable, the solution may be readily prepared and handled. In addition, the solution of optically active glutamate to be added may be unsaturated, saturated or supersaturated as long as the solution becomes supersaturated with race-mate after being mixed with the solution of an optically active isomer. For eflecting an ellicient resolution, the degree of supersaturation of the solution after the introduction of the solution containing an optical enantiorner should be as high as possible. The amount of the optically active glutamic acid salt in the supersaturated solution should be not less than 2% by weight based on the amount of racemate and preferably not more than 50%, since any amount beyond 50% does not contribute to the efliciency of resolution and is not economically advantageous. The concentration of an optically active glutamic acid salt in the solution into the racemate solution should be as high as possible, practically in the range from 50 to 200% by weight, for increasing efiiciency of resolution.

Resolution according to this invention takes place remarkably well with the hydrochloride or ammonium salt of racemic glutamic acid which have greater solubility than that of the corresponding optically active isomers. Although the conventional selective crystalization method comprising seeding with optically pure crystals has been carried out in the pH range at which glutamic acid separates in free form, the resolution in such a pH range is a practically impossible by the process of this invention which introduces optically active glutamic acid not in the form of crystals but in the form of a solution. Thus the successful application of this invention is limited only to solutions of glutamic acid salts. The present process can also be applied to an aqueous glutamic acid hydrochloride solution having free hydrochloric acid or not. Furthermore, the present process can be applied to an aqueous ammonium glutamate solution containing free ammonia or not.

The degree of supersaturation of racemate in solution may be advantageously regulated in the range from about 105 to 200% of the saturation level at the temperature of resolution. supersaturation of a lower degree than specifled above necessitates a greater amount of the optically active species, lengthens the induction period for development of crystalline nuclei, decreases the yield of the desired optically active isomer per volume of solution, which result in a marked decrease of resolution efficiency; and, supersaturation of a greater degree than specified above causes premature crystalization of the undesired isomers, thus making the period of separating solid from liquid too long and sometimes leading to failure of resolution.

Preferably the degree of supersaturation of racemate is about l-160%.

The concentration of the racemate solution, and the concentration and amount of the optically active isomer determine the induction period, i.e., the period of time before which optically active crystalline nuclei appear, and the period of time in *which only the desired optically active isomer nuclei grow. After this period, another optically active isomer usually starts to crystalize. Furthermore, by suitable selection of the degree of supersaturation of racemate and the amount and concentration of the optically active isomer, it is possible to selectively crystalize the isomer which has been added and to predict and regulate the period necessary for attaining maximum yield of the optically active isomer since individual crystalline particles usually grow uniformly. The induction period preceding the appearence of crystalline nuclei changes according to the degree of supersaturation of racemate solution and the amount and the concentration of optically active isomer: if the latter two factors are kept constant, the induction period becomes shorter as racemate concentration increases; and, if the racemate concentration is kept constant, the period becomes shorter as the amount and concentration of the optically active isomer increase. For effecting the development and growth of the crystals in homogeneous and reproducible manner, strict control of temperature and the concentrations of each component, higher purity of the employed glutamate, complete avoidance of foreign materials from the mixed solution, employment of an unmarred container and controlled stirring speed are required. Although these requirements are not considered completely realizable in commercial scale, we have now found that treatment with ultrasonic waves at the time of nuclei formation makes possible reproducible and reliable timecourse development and growth of crystalline nuclei of the desired optically active isomer in preference to crystals of another optically active isomer and/ or racemate isomer, even if the above noted conditions should fluctuate to some extent.

Although the agglomerative effect of ultrasonic waves is well known in the art, we have found that the treatment of the supersaturated solution containing racemate and an optically active isomer respectively in concentrations as specified above with ultrasonic waves invariably causes homogeneous development of many microcrystalline nuclei of the desired optically active isomer without being contaminated by racemate. Furthermore, even with a solution containing racemate at so low a concentration as to require a longer induction period, Which results in an appreciable fluctuation in the crystallization period,

ultrasonic waves successfully cause reliable and homogeneous development and growth of microcrystalline nuclei throughout the solution in a short period of time. The period for treatment with ultrasonic waves is usually no longer than 30 min, practically from O to 5 minutes. The frequency of the ultrasonic waves may be about 5-500 kilocycle, preferably about 10-100 kilocycle. Again, the period of time for achieving a maximum yield of resolution varies depending on the degree of supersaturation and the amount and the concentration of the solution of the optically active isomer. As long as the concentration and the amount of the optically active isomer is maintained constant, a higher degree of supersaturation is usually followed by shorter period for attaining a maximum resolution and higher yield per liquid volume. On the other hand, with determined concentrations of racemate and optically active isomer, a limited increase in the amount of the optically active isomer shortens the period of resolution, but, beyond a limited range, the recovery of optically active isomer per solution volume, and the efficiency both decrease.

The period for attaining maximum resolution is in the range from about 0.5 to min., with the above specified degree of saturation and the amount of the optically active isomer.

For example, the periods of time required for attaining a maximum degree of resolution from the time when nuclei appeared obtained by introducing 15 g. of an aqueous saturated solution containing 4.85 g. of L-glutamic acid hydrochloride to racemate solutions containing 106 g./l00 g. (150% of the just saturated concentration 70.7 g./100 g.) and 91.9 g./100 g. saturation) of racemate salt respectively while keeping the temperature at 25 C. were found to be 2.4 min. and 6 min. respectively with yields of 17.8 g. and 9.5 g. Increasing the concentration of optically active isomer further shortened the period of time for achieving maximum resolution, thus a period of less than 1 min. is possible under suitable conditions.

The period for achieving maximum resolution, that is, the period prior to separation of solid phase from liquid phase varies not only according to the above described factors, i.e. the degree of supersaturation of racemate and the quantity and the concentration of the optically active isomer, but also varies according to the manner of cooling the solution, and regulating the temperature of the mixed solution which is inevitably elevated by the heat of crystallization generated on the formation of a large amount of crystals in a short period of time. Furthermore, even with the same degree of supersaturation and the concentrations and the amount of the optically active isomer, the period varies according to the scale of operation. The period tends to increase with the increase of the operative scale due to the slower rate of removal of heat of crystallization.

The above-described method of resolution proceeds equally as well in the case of previously placing an optically active isomer in a supersaturated solution or in the case of introducing a solution of an optically active isomer to a supersaturated solution containing the optically active isomer besides racemate; the coexisting optically active isomer crystallizes in preference to the racemate, which crystals grow rapidly, resulting in resolution of the racemate.

The theoretical yield of resolution which is equal to one half of the difference between the amount of the racemate in the original supersaturated solution and the amount that would be present in a state of saturation at resolution temperature may be attained readily by the process of this invention. Sometimes, a yield of even more than that may be obtained in a very short period of time, if the degree of supersaturation of racemate and the amount and the concentration of the optically active isomer in the introduced solution are suitably regulated so as to give rise to a rapid and homogeneous development and growth of many micro-crystalline nuclei. There sometimes even occurs a lapse of time between the end of the crystallization of the optically active isomer and the onset of the crystallization of another isomer left in the mother liquor. An additional advantage of operation under the optimal conditions stated above, is that the amount of racemate remaining in the mother liquor after the crystallization of more than theoretical amount of the desired optically active isomer decreases below saturation concentration. Such a decrease in the amount of racemate insures that the other undesired isomer remains in the solution. These advantages of the process of this invention contributes to the eflicient recovery of the desired optically active isomer of very high purity, even from a solution supersaturated to an extreme degree.

As still another advantage of this invention, the crystal size distribution of crystals becomes more even due to homogeneous development and growth of countless microcrystals. The crystal size may be regulated so as to increase the suspendability of crystalline particles, which in turn improves the transportability of crystal slurries, and provides for liquid with a constant amount of solid suspended therein for the separation step, and makes the separation of crystal from slurry easier. Such regulation of crystal size is also possible by controlling the degree of super saturation of racemic glutamic acid salt and the concentration and the amount of the optically active isomer to be introduced within the above specified range.

Control of the resolution may be more readily achieved by introducing a solution of an optically active isomer to a supersaturated solution of racemic glutamic acid salt than by previously placing said optically active isomer in a supersaturated solution. Extremely improved resolution etficiency may be achieved by introducing the solution of an optically active isomer to the supersaturated solution containing the same form of optically active isomer additionally.

Resolution may be conveniently carried out at 80 C., preferably at an ambient temperature from 20 to 30 C., and even lower temperatures.

For maintaining suitable degrees of supersaturation of mother liquor during the progress of the resolution, the following methods may be convenient.

In the resolution of glutamic acid hydrochloride, a suitable degree of supersaturation may be maintained by gradually adding hydrogen chloride up to a concentration no higher than 20% by weight to the system. At concentrations of hydrogen chloride beyond this range, the solubility of racemic hydrochloride becomes substantially the same as that of free acid, with the result that the advantage of the present process with respect to yield per unit volume of solution is negated.

In'the process using ammonium salt of glutamic acid, the existence of an excessive amount of ammonia reveals not only the effects of maintaining suitable degrees of supersaturation and controlling the concentration of racemate, but the advantages of controlling the viscosity of solution in favorably influencing the development and growth of crystalline nuclei. As in the case of hydrochloric acid, ammonia may be added along with the progress of resolution in order to maintain the degree of supersaturation higher than about 105%. Again, the concentration of ammonia should not exceed about 20 by weight, since ammonia concentration cannot be controlled beyond this range due to the inevitable dissipation of ammonia at operating temperatures repeatedly elevated and lowered within the range of 0-80 C., usually l0-60 C.

The desired degree of supersaturation may also be rna'mtained by concentrating the solution or gradually cooling the solution along with the progress of resolution.

The degree of supersaturation as used in this specification and appended claims may be defined as c/c x 100 6 wherein C is the amount in grams of DL-glutamic acid salt per g. of water or solvent and C is the amount in grams of DL-glutamic acid salt per 100 g. of water or solvent of saturated solution.

EXAMPLE 1 To a solution obtained by dissolving 106 g. of DL-glutamic acid hydrochloride in 100 ml. of water at 55 C. and rapidly cooled to 25 C. was added an aqueous saturated solution containing 4.7 g. of L-glutamic acid hydrochloride in 10 g. of water prepared at 24 C. and adjusted to 25 C., under agitation at this temperature.

After 6 minutes, the resulting crystals were filtered. The recovered crystals weighed 18.7 g., exhibited M1 +25 and an optical purity of 96.7%. The substantial yield of pure L-isomer not comprising the added L-isomer was 13.55 g., corresponding to the degree of resolution of 96.7%.

The mother liquor of resolution was stirred at 25 C. for 20 minutes and the resulting crystals filtered and dried. The product weighed 13.9 g. and exhibited [0c] =24.8 and an optical purity of 96.6%. Thus, the amount of recovered pure D-glutamic acid was 13.4 g., corresponding to 95.9% of the D-isomer which was present in the mother liquor after resolution. The rate of resolution as used in the present specification may be calculated according to the formula:

The degree of resolution CLUB 100 wherein W :Tl1e amount of the pure optically active isomer recovered by resolution. W zThe amount of the optically active isomer added to or made to preexist in the supersaturated solution.

EXAMPLE 2 To an aqueous solution obtained by dissolving 117 g. of DL-glutamic acid hydrochloride in 100 g. of water at 60 C. and rapidly cooled to 25 C. was added a saturated solution obtained by dissolving 4.8 g. of L-glutamic acid hydrochloride in 10 g. of water and adjusted to 25 C. and stirred. The crystals were filtered after 5 minutes of stirring, washed with a small amount of cold water and dried. The dried product weighed 31.1 g. and exhibited [a] =+24.4 and an optical purity of 95.2%, thus the substantial yield being 25.0 g. and the degree of resolution being 108% 7 EXAMPLE 3 A solution obtained by dissolving 318 g. of DL-glutamic acid hydrochloride in 300 g. of water at 55 C. was divided into three equal portions. The three portions were rapidly cooled to 25 C. and treated respectively with 10 g., 20 g. and 30 g. of L-glutamic acid hydrochloride, each having been dissolved in the same weight of water. The resulting mixtures were maintained at a temperature of 25 C. by circulating water at 25 C. around the container and allowed to stand for periods of 2.5, 3 and 4% minutes respectively. At the end of the respective time periods, the resulting crystals were filtered and dried.

The result of these runs was as follows:

EXAMPLE 4 ()nc hundred grams of DL-glutamic acid hydrochloride and g. of L-glutamic acid hydrochloride were dissolved in 100 g. of water at 65 C. and stirred in a bath maintained at 30 C. After 12 min., when the temperature reached 38.5 C., the resulting crystals were separated. Yield: 26.9 g. [a] =+24.9.

EXAMPLE 6 A solution obtained by dissolving 1070 g. of DL-glutamic acid hydrochloride (containing 8.6 g. of L-glutamic acid hydrochloride) in 1000 m1. of water at 55 C. was rapidly cooled to 25 C., followed by the treatment with 100 g. of an aqueous solution containing 51.5 g. of L-glutamic acid hydrochloride at a temperature of 25 C. The resulting mixture was further stirred at 25 C. After 7 min., the crystals were separated by ccntrifugation. Yield:

198 g.; [a] =+24.65; and an optical purity of 96.4%.

EXAMPLE 7 504 g. of a solution of DL-ammonium glutamate saturated at 58 C. was cooled down to 30 C. and 20 g. of a solution saturated with 8.9 g. of ammonium L-glutamate at 30 C. was added thereto. Stirring was continued at 30 C. and crystals were filtered after 15 minutes of stirring. Recovered crystals weighed 23.1 g. and possessed an optical purity of 95.3%.

EXAMPLE 8 A clear solution prepared by adding 154 ml. of water to 392 g. of DL-glutarnic acid monohydrate, adjusting to pH 8.0 with concentrated aqueous ammonia and effecting dissolution by warming was cooled to 20 C. and treated with 45.7 g. of an aqueous solution saturated with L-monoammonium glutamate at C. (a concentration of 82.7 g./ 100 g. water). Crystals were separated after 23 minutes of stirring at 20 C., washed with methanol and dried.

Recovered L-monoammonium glutamate monohydrate weighed 68.1 g. and possessed an optical purity of 87.1%.

EXAMPLE 9 A solution prepared by dissolving 53 g. of DL-glutamic acid hydrochloride in 50 ml. of water by warming was placed in an ultrasonic wave generator provided with circulating water at 25 C., whereby the warmed solution was cooled to 25 C., and 7.4 g. of an aqueous solution saturated with L-glutamic acid hydrochloride at 25 C. was added thereto.

The solution was treated for sec. with ultrasonic waves at an intensity of 115 ma. (The employed ultrasonic wave generator had a wave number of 10 kc. and the power was represented in the term of the current value,

ma., i.e. in milliamperes. After the treatment, gentle stirring was continued for 2.5 min. and the resulting slurry was separated into solid and liquid phases.

The recovered crystals weighed 9.0 g. after drying and contained 96.8% of L-glutamic acid hydrochloride.

EXAMPLE 10 The starting material was the same as that employed in Example 1 and was treated with an ultrasonic wave at an intensity of ma. for 3 min., while the temperature was maintained at 25 C. with circulating water.

Separation of the resulting slurry into solid and liquid gave 9.4 g. of dried crystals with an optical purity of 96.6%.

EXAMPLE 11 A solution prepared by dissolving 42.4 g. of DL-glutamic acid hydrochloride and 2 g. of D-glutamic acid hydrochloride in 50 g. of water under warming was placed in an ultrasonic wave generator provided with circulating water at 25 C. and, after the temperature of the solution was equilibrated, it treated for 1 min. with the ultrasonic wave at an intensity of 1.50 ma. After gentle stirring for 8 min., the resulting slurry was separated into solid and liquid phases. Recovered crystals weighed 8.7 g. and contained 98.7% of D-glutamic acid hydrochloride.

In a control run employing the same materials and conditions but avoiding the treatment with ultrasonic wave, homogeneous development of microcrystalline nuclei hardly occurred; only several crystals appeared after 30 min. as long of period and still with marked fluctuation in the induction period and the amount of crystals.

EXAMPLE 12 A solution prepared by dissolving a mixture comprising 20 g. of DL-glutamic acid hydrochloride and 1.5 g. of D-glutamic acid hydrochloride in 50 m1. of aqueous hydrochloric acid 10% by weight was placed in an ultrasonic wave generator provided with circulating water at 20 C., cooled therein to 20 C., treated with an ultrasonic wave at an intensity of 80 ma. for 10 sec. and thereafter gently stirred for 2.5 min. The resulting slurry was separated into solid and liquid phases. The recovered crystals weighed 7.3 g. and contained 94.3% of D-glutamic acid hydrochloride.

EXAMPLE 13 An aqueous solution prepared by dissolving and mixing 5 g. of ammonium L-glutamate monohydrate crystals in g. of an aqueous solution containing 55 g. (as anhydrate) of ammonium DL-glutamate was placed in an ultrasonic wave generator provided with circulating water at 10 C., treated for 3 min. with ultrasonic wave at an intensity of 150 ma. and thereafter gently stirred for 15 min. The resulting slurry was separated into solid and liquid phases and the crystals were washed with methanol and dried. The recovered crystals weighed 11.5 and contained 96.9% of ammonium L-glutamate monohydrate.

From the above description, those skilled in the art will understand the spirit, the aspects and the advantages which are unique to this invention.

What we claim is:

1. A process for resolving a racemic salt of glutamic acid, said salt being selected from the group consisting of hydrochloride and ammonium salts which comprises forming an aqueous supersaturated solution of the racemic salt and one optically active isomer of said salt, the concentration of the racemic salt being 5-100% greater than the concentration of a saturated solution of said racemic salt, and the amount of said one optically active isomer being 2-50% by weight of the racemic salt, maintaining the temperature of said solution between 080 C. for a period of 0.5- minutes during which period nuclei of crystals of said one optically active isomer form and grow into crystals of optically active isomer to form a slurry of said crystals, and separating the crystals from the slurry before formation of crystals of the other optically active isomer.

2. A process as claimed in claim 1, wherein the supersaturated solution is formed by dissolving in water the racemic salt and the optically active isomer.

3. A process as claimed in claim 1, wherein the supersaturated solution is formed by dissolving in water the racemic salt and the optically active isomer, and adding to the thusly formed solution a solution of the optically active isomer.

4. A process as claimed in claim 1, wherein the supersaturated solution is formed by dissolving in water the racemic salt, and adding to the thusly formed solution a solution of the optically active isomer.

5. A process as claimed in claim 1, wherein the racemic salt of glutamic acid is the hydrochloride.

6. A process as claimed in claim comprising controlling the degree of supersaturation of the solution by adding hydrochloric acid dropwise to said solution.

7. A process as claimed in claim 6, wherein the amount of hydrochloric acid added is up to 20% by weight.

8. A process as claimed in claim 1, wherein the racemic salt of glutamic acid is the ammonium salt.

9. A process as claimed in claim 8 comprising controlling the degree of supersaturation of the solution by adding ammonia dropwise to said solution.

10. A process as claimed in claim 9, wherein the amount of ammonia added is up to 20% by weight.

11. A process as claimed in claim 1, wherein the temperature is maintained constant.

12. A process as claimed in claim 1 comprising lowering the temperature of the solution during the period in which crystals of the optically active isomer grow, thereby controlling the degree of supersaturation of said solution.

13. A process as claimed in claim 1 comprising concentrating the solution during the period in which crystals of the optically active isomer grow, thereby controlling the degree of supersaturation of said solution.

14. A process as claimed in claim 1, wherein the solution maintained at 080 C. is irradiated with ultrasonic waves to initiate formation of nuclei of crystals of said one optically active isomer.

15. A process as clarned in claim 14, wherein the solution is irradiated with ultrasonic waves for a period of up to 30 minutes.

16. A process as claimed in claim 14, wherein the solution is irradiated with ultrasonic waves for a period of 1 second to 3 minutes.

17. A process as claimed in claim 14, wherein the ultrasonic waves are of a freqnuency of 5500 kilocycles.

18. A process as claimed in claim 14, wherein the ultrasonic waves are of a frequency of 10-100 kilocycles.

References Cited UNITED STATES PATENTS 3/1952 Tournier 23-301 6/1961 Purvis 260534 

1. A PROCESS FOR RESOLVING A RACEMIC SALT OF GLUTAMIC ACID, SAID SALT BEING SELECTED FROM THE GROUP CONSISTING OF HYDROCHLORIDE AND AMMONIUM SALTS WHICH COMPRISES FORMING AN AQUEOUS SUPERSATURATED SOLUTION OF THE RACEMIC SALT AND ONE OPTICALLY ACTIVE ISOMER OF SAID SALT, THE CONCENTRATION OF THE RACEMIC SALT BEING 5-100% GREATER THAN THE CONCENTRATION OF A SATURATED SOLUTION OF SAID RACEMIC SALT, AND THE AMOUNT OF SAID ONE OPTICALLY ACTIVE ISOMER BEING 2-50% BY WEIGHT OF THE RA CEMIC SALT, MAINTAINING THE TEMPERATURE OF SAID SOLUTION BETWEEN 0-80*C. FOR A PERIOD OF 0.5-120 MINUTES DURING WHICH PERIOD NUCLEI OF CRYSTALS OF SAID ONE OPTICALLY ACTIVE ISOMER FORM AND GROW INTO CRYSTALS OF OPTICALLY ACTIVE ISOMER TO FORM A SLURRY OF SAID CRYSTALS, AND SEPARATING THE CRYSTALS FROM THE SLURRY BEFORE FORMATION OF CRYSTALS OF THE OTHER OPTICALLY ACTIVE ISOMER.
 14. A PROCESS AS CLAIMED IN CLAIM 1, WHEREIN THE SOLUTION MAINTAINED AT 0-80*C. IS IRRADIATED WITH ULTRASONIC WAVES TO INITIATE FORMATION OF NUCLEI OF CRYSTALS OF SAID ONE OPTICALLY ACTIVE ISOMER. 